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As late as the 1800s, causes and cures of TB remained mysterious - PowerPoint PPT Presentation


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As late as the 1800s, causes and cures of TB remained mysterious. Then along came Robert Koch. December 11, 1843- May 27, 1910. You may not remember me but I ’ ll bet you ’ ve heard of my Postulates. I developed tests to determine whether an infectious agent causes a given disease.

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Presentation Transcript
slide1

As late as the 1800s, causes and

cures of TB remained mysterious

slide2

Then along came

Robert Koch

December 11, 1843-

May 27, 1910

slide3

You may not remember me but

I’ll bet you’ve heard of my Postulates

slide4

I developed tests to determine

whether an infectious agent

causes a given disease

slide5

1.The microorganism must be found in abundance

  • in all organisms suffering from the disease,
  • but not in healthy organisms.
slide6

1.The microorganism must be found in abundance

  • in all organisms suffering from the disease,
  • but not in healthy organisms.

2.The microorganism must be isolated

from a diseased organism and grown

in pure culture

slide7

1.The microorganism must be found in abundance

  • in all organisms suffering from the disease,
  • but not in healthy organisms.

2.The microorganism must be isolated

from a diseased organism and grown

in pure culture

3.The cultured microorganism should

cause disease when introduced into a

healthy organism.

slide8

1.The microorganism must be found in abundance

  • in all organisms suffering from the disease,
  • but not in healthy organisms.

2.The microorganism must be isolated

from a diseased organism and grown

in pure culture

3.The cultured microorganism should

cause disease when introduced into a

healthy organism.

4.The microorganism must be re-isolated

from the inoculated, diseased

experimental host and identified

as being identical to the original

specific causative agent.

slide9

I know it’s a hard act to follow,

but I wasn’t done yet

In 1882 while working in Berlin

I discovered the tuberculosis bacteria

and the means of culturing it

slide10

The Nobel Prize in Physiology or Medicine

1905

In 1882 while working in Berlin

I discovered the tuberculosis bacteria

and the means of culturing it

Nobelprize.org

slide11

Our star: Mycobacterium Tuberculosis

Aren’t I pretty?

Mycobacterium Tuberculosis on Lowenstein-Jensen medium

Mycobacterium Tuberculosis (scanning EM)

Images from CDC

slide12

But I am very hard to grow

Mycobacterium Tuberculosis on Lowenstein-Jensen medium

Mycobacterium Tuberculosis (scanning EM)

Images from CDC

slide13

I am an Obligate aerobe and grow very slowly

15-20 hour doubling vs. 30 minutes for E. coli

I require 6-8 weeks to grow on plates!

Mycobacterium Tuberculosis on Lowenstein-Jensen medium

Mycobacterium Tuberculosis (scanning EM)

Images from CDC

slide14

I am ‘acid-fast” so you can

ID me using special stains

Mycobacterium Tuberculosis on Lowenstein-Jensen medium

Mycobacterium Tuberculosis (scanning EM)

Images from CDC

slide15

Acid-fastness refers to resistance to decolorization

by acids during staining procedures

The most common staining technique is Ziehl-Neelsen stain,

in which the bacteria are stained bright red.

Red is my favorite color!

Mycobacterium tuberculosis (stained red) in tissue (blue).

Mycobacterium tuberculosis (stained red) in sputum

slide16

Here’s my family tree

Staph. aureus

TB bug

E. coli

Genome Research 12, 1080-1090 (2002)

slide17

We’re distant cousins

Staph. aureus

TB bug

E. coli

You

Genome Research 12, 1080-1090 (2002)

slide18

Mycobacterial relatives

of the TB bug cause other diseases

Mycobacterium africanum: causes up to one-third

of TB cases in West Africa.

Milder in non-immunocompromised patient

Mycobacterium leprae causes Leprosy (Hansen’s disease)

slide19

Mycobacterial relatives

of the TB bug cause other diseases

Mycobacterium africanum: causes up to one-third

Of TB cases in West Africa.

Milder in non-immunocompromised patient

Mycobacterium leprae causes Leprosy (Hansen’s disease)

Mycobacterium bovis. Causes Bovine TB. Killed many

farm animals inn first half of 20th century.

Destroyed by pasteurization. Causes TB in developing world.

Mycobacterium avium. Causes TB in birds. Also

affects HIV patients and other immunocompromised people

slide20

Here’s how it usually starts

Left untreated, a person with active TB

will infect 10-15 other people per year

World Lung Foundation (2008) and http://pathport.vbi.vt.edu/pathinfo/pathogens/Tuberculosis_2.html

slide22

It takes advantage of our bodies

own “first-responders”

Macrophage

slide23

Macrophages are responsible for

Phagocytosis of bacteria

and other foreign cells and for activation

of other immune cells

Macrophage

Bacteria

slide24

Macrophages love to “eat” bacteria

Yum-yum!

www.nyas.org/.../ images/carroll3_small.jpg

slide25

Macrophages bind to mannosyl oligosaccharide residues

on the bacterial cell surface using their

cell surface mannose receptors

Yum-yum!

Clin Microbiol Rev. 2003 July; 16(3): 463–496.

slide26

Normally ingested

bacteria and

other things get sent

to the lysosome

for destruction

by low pH and

proteolysis

Uh oh!

bacterium

Ahhhhhhh…..

slide27

But the TB bacterium

has a better idea--

It remodels the

endosome to be its

new home!

Very cozy

slide28

Avoiding the lysosome

also reduces presentation

of bacterial peptides

to the immune system by

the MHC proteins

Very cozy

slide29

How does it do that?

Let’s look for a

mutant bacteria

that can’t avoid

destruction!

Very cozy

slide30

How does it do that?

Let’s look for a

mutant bacteria

that can’t avoid

destruction!

slide31

Here’s the bacterial

protein required—

mutate it and

Mycobacteria

end up in

lysosome

PknG!!

slide32

PknG is a

Serine-threonine

Kinase!

But wait….

Bacteria don’t have them!

slide33

Even cooler, it has other

Domains found in NO

Other kinases

One may make it re-dox

regulated

slide35

Bacteria

Inject

proteins

INTO

Our cells!!

PknG is

One such

protein

slide36

The infected macrophage calls for help,

generating a granuloma

www.nyas.org/.../ images/carroll3_small.jpg

slide38

Infected macrophages send signals

that recruit nearby lymphocytes

slide39

Uninfected macrophages and

Lymphocytes surround the infected cells

slide40

They encase the infected cells in a

“cage” of “extracellular matrix” proteins

where they can stay for years!

slide41

We’re actually quite good at keeping TB at bay

only one-third of exposed patients

will become infected and only 3-5%

develop TB in the first year

Clin Microbiol Rev. 2003 July; 16(3): 463–496.

slide42

We can harness the immune response

To help fight TB

Albert Calmette

Camille Guérin

slide43

We can harness the immune response

To help fight TB

Bacillus Calmette-Guérin = BCG!

Albert Calmette

Camille Guérin

slide44

Bacillus Calmette-Guérin = BCG!

An “attenuated” strain of M tuberculosis that does not

Cause disease but can stimulate the immune response

http://www.cheng.cam.ac.uk/

slide45

Bacillus Calmette-Guérin = BCG!

Interestingly, all “attentuated” strains have a common deletion

In the genome, removing at least one known “virulence” gene

Clin Microbiol Rev. 2003 July; 16(3): 463–496.

slide46

Bacillus Calmette-Guérin = BCG!

BCG is clearly effective against miliary TB and TB meningitis

But its effectiveness against pulmonary TB is controversial

http://www.cheng.cam.ac.uk/

slide47

New attenuated strain vaccines and recombinant versions of

BCG are now in Phase II and Phase III clinical trials

Image from University of Oxford

slide48

Even without vaccination, in most

otherwise healthy people

the immune system keeps TB at bay

slide49

But if the immune system is compromised

by malnutrition, HIV or old age….

slide51

There is still much to be learned!

“What makes M. tuberculosis virulent?

Unfortunately, there is no simple answer yet,

despite the knowledge obtained in

the last 100 or more years”

Clin Microbiol Rev. 2003 July; 16(3): 463–496.

slide52

We do know certain things

Uncontrolled M. tuberculosis growth is associated

with extensive lung damage that ultimately causes

death by suffocation.

Clin Microbiol Rev. 2003 July; 16(3): 463–496.

slide53

We do know certain things

Uncontrolled M. tuberculosis growth is associated

with extensive lung damage that ultimately causes

death by suffocation.

Inflammatory responses are important in pathogenesis

in brain and bone.

Clin Microbiol Rev. 2003 July; 16(3): 463–496.